The nuclear lamina (NL) is a protein meshwork lining the nuclear envelope (NE) that contains a polymer of nuclear lamins and associated proteins, including transmembrane proteins of the inner nuclear membrane (INM). The NL provides a scaffold for the NE, regulates its mechanical and dynamic properties, and modulates the activity of signaling and transcriptional pathways. The NL has well-recognized importance in the biology of higher eukaryotes, as underscored by the association of over 15 human genetic diseases with mutations in NL proteins. Although major proteins and general properties of the NL have been characterized in animal and cultured cell models, a detailed molecular understanding of how specific NL components control nuclear functions is only beginning to be developed. This project builds on the finding that the NL protein Lem2, encoded by the Lemd2 gene, regulates three major MAP kinase (MAPK) families in cells, ERK, p38 and JNK. Work demonstrated that Lemd2 is vital for mouse embryogenesis and heart development, that disruption of Lemd2 in adult liver results in metabolic derangements, and that knockout in skeletal muscle causes a dystrophic phenotype. The project is focused on obtaining a molecular understanding of how Lem2 controls MAPK signaling in cells and adult tissues of mouse. One Aim is directed at understanding the mechanisms by which Lem2 regulates the activity of ERK, p38, and JNK MAPKs using Lemd2-null mouse embryo fibroblasts (MEFs) reconstituted with Lem2 mutants. Potential effectors of ERK regulation by Lem2 will be identified by candidate and discovery-based approaches, and the validity of candidate effectors will be examined with a battery of functional tests. The findings on ERK regulation will be extended to an analysis of the related p38 and JNK MAPKs. A second Aim involves studying the functions of Lem2 in the biology of liver and skeletal muscle using mouse strains with tissue-specific knockouts of the Lemd2 gene. The metabolic defects with a liver-specific disruption of Lemd2, which are correlated with elevated p38, will be characterized in detail. These results will be applied to mechanistic analysis of Lem2 functions related to glucagon signaling in primary hepatocytes from Lemd2 liver-knockout animals. In separate studies, the dystrophic phenotype in a mouse strain with a skeletal muscle-specific disruption of Lemd2 will be characterized by analysis of muscle physiology and signaling pathways. The work will be directed at understanding how aberrant signaling caused by loss of Lem2 gives rise to muscle defects. Altogether, these studies should afford refined molecular insight on how signaling is controlled by a specific NL protein- Lem2- and how defects in this control become manifest in different mouse tissues.